Rivaroxaban in patients with abdominal aortic aneurysm and high-sensitivity C-reactive protein elevation (BANBOO): study protocol for a randomized, controlled trial

Background Abdominal aortic aneurysm (AAA) is a fatal disease due to the tendency to rupture. The drug treatment for small AAA without surgical indications has been controversial. Previous studies showed that high-sensitivity C-reactive protein (hs-CRP) had become a potential biomarker of the disease, and the anti-inflammatory effect of rivaroxaban for AAA had been well established. Thus, we hypothesized that rivaroxaban could control the progression of AAA in patients with hs-CRP elevation. Methods The study is a prospective, open-label, randomized, controlled clinical trial. Sixty subjects are recruited from the General Hospital of Northern Theatre Command of China. Subjects are randomly assigned (1:1) to the intervention arm (rivaroxaban) or control arm (aspirin). The primary efficacy outcome is the level of serum hs-CRP at 6 months. The secondary outcomes include imaging examination (the maximal diameter of AAA, the maximal thickness of mural thrombus, and the length of aneurysm), major adverse cardiovascular and cerebrovascular events (MACCE, including AAA transformation, non-fatal myocardial infarction, acute congestive heart failure, stent thrombosis, ischemia-driven target vessel revascularization, vascular amputation, stroke, cardiovascular death, and all-cause death), and other laboratory tests (troponin T, interleukin 6, D-dimer, and coagulation function). Discussion The BANBOO trial tested the effect of rivaroxaban on the progression of AAA in patients with elevated Hs-CRP for the first time. Trial registration ChiCTR2100051990, ClinicalTrials.gov, registered on 12 October 2021. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-023-07461-3.


Appendix B. Endpoints' definitions of the BANBOO trial.
1. The level of serum hs-CRP at 6 months Three value of serum hs-CRP will be recorded at entry, 1month and 6 months in the BANBOO trial. Immuno-turbidity is used to detect serum hs-CRP concentration, measured in mg/L.

Imaging examination
The maximal orthogonal AAA diameter on computerized tomography angiography (CTA) is a measurement of infrarenal aortic diameter perpendicular to the lumen, devised to avoid overestimation of tortuous AAAs, the largest orthogonal diameter is taken to be the maximal diameter of AAA. [Morris et al. TEDY. Trials (2015) 16:274. doi: 10.1186/s13063-015-0793-z] The maximal thickness of mural thrombus is measured in the whole region of abdominal aorta (upper diaphragm, lower common iliac artery), not restricted at the site of maximal diameter.
The length of aneurysm is measured between the sites widen compared with the normal abdominal aorta, take care to correct tortuous part of AAAs by software (GE AW4.4 postprocessing workstation).

Major adverse cardiovascular and cerebrovascular event (MACCE)
3.1 AAA transformation AAA transformation is defined as AAAs develop into aortic dissection, penetrating ulcer, intramural hematoma, pseudoaneurysm and intraperitoneal hyperemia. Type 1 MI: spontaneous MI related to ischemia due to a primary coronary event such as plaque erosion and/or rupture, fissuring or dissection.
Type 2 MI: MI secondary to ischemia due to either increased oxygen demand or decreased supply.
Type 3 MI: death occurring before blood samples could be obtained, or at a time before the appearance of cardiac biomarkers in the blood. Reduced LVEF is defined as ≤40%, i.e. those with a significant reduction in left ventricular (LV) systolic function. This is designated as HFrEF.
Patients with a LVEF between 41% and 49% have mildly reduced LV systolic function, i.e.
HFmrEF. Retrospective analyses from RCTs in HFrEF or CHF with preserved ejection fraction (HFpEF) that have included patients with ejection fractions in the 40-50% range suggest that they may benefit from similar therapies to those with LVEF≤40%.This supports the renaming of HFmrEF from 'heart failure with mid-range ejection fraction' to 'heart failure with mildly reduced ejection fraction'.
Those with symptoms and signs of CHF, with evidence of structural and/or functional cardiac abnormalities and/or raised natriuretic peptides, and with an LVEF≥50%, have HFpEF.

Stent thrombosis
Stent thrombosis is defined according to the definite or probable criteria of the Academic Research Consortium (Circulation 2007;115:2344-51).

Definite stent thrombosis
Presence of an ACS with angiographic or autopsy evidence of thrombus or occlusion.

Probable stent thrombosis
Unexplained death within 30 days after the procedure, or acute myocardial infarction involving the target-vessel territory without angiographic confirmation.

Possible stent thrombosis
All unexplained death occurring at least 30 days after the procedure. Stent thrombosis classification by time frame： 1) Acute stent thrombosis Occurring within 24 hours after the index PCI.
2) Subacute stent thrombosis Occurring between 24 hours and 30 days after the index PCI.

3) Late stent thrombosis
Occurring between 31 and 360 days after the index PCI.

4) Very late stent thrombosis
Occurring later than 360 days after the index PCI.

Ischemia-driven Target Vessel Revascularization (ID-TVR)
Ischemia-driven target vessel revascularization is defined as repeat PCI or bypass surgery of the target lesion(s) and any additional lesions in the main epicardial coronary artery or branches containing the target lesion, with one or more of the following conditions: 1) Patient had ischemic symptoms and ECG-changes referable to the target lesion.
2) Diameter stenosis≥50% at follow-up angiography and a positive functional study corresponding to the area served by the target vessel.
3) Diameter stenosis<50% at follow-up angiography but a markedly positive functional study or ECG-modification corresponding to the territory supplied by target vessel. 4) Diameter stenosis≥70% at follow-up angiography in absence of documented clinical or functional ischemia.

Stroke
Neurological dysfunction caused by acute focal lesions of the central nervous system due to vascular etiology, including hemorrhagic stroke and ischemic stroke. Patients present as sudden onset of vertigo, numbness, aphasia, dysarthria or central neurologic deficit secondary to vascular lesions of the brain such as hemorrhage, embolism, thrombosis, or rupturing aneurysm.

Cardiovascular death
Cardiovascular death is defined as death due to myocardial infarction, cardiac perforation or tamponade, arrhythmia, stroke during follow-up period, death due to a complication of the cardiovascular drugs allocated to subjects, and any death in which a cardiac cause cannot be excluded.
3.9 All-cause death Deaths that are not caused by definite non-cardiac factors are deemed as cardiac deaths.
Specifically, any unexpected deaths in subject are deemed as cardiac deaths, even if they also have potential fatal non-cardiac diseases (for example, cancer and infection). Type 0: no evidence of bleeding.
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional.
Type 2: any clinically overt sign of hemorrhage (eg, more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that is actionable but does not meet criteria for type 3, type 4, or type 5 BARC bleeding. The bleeding must meet at least one of the following criteria: First, it requires intervention, defined as a health care professional guided medical treatment or percutaneous intervention to stop or treat bleeding, including temporarily or permanently discontinuing a medication or study drug. Second, the bleeding leads to hospitalization or an increased level of care, defined as leading to or prolonging hospitalization or transfer to a hospital unit capable of providing a higher level of care. Or third, the bleeding prompts evaluation, defined as leading to an unscheduled visit to a healthcare professional resulting in diagnostic testing. Reoperation after closure of sternotomy for the purpose of controlling bleeding; Transfusion of ≥5 U whole blood or packed red blood cells within a 48-hour period; Chest tube output ≥2 L within a 24-hour period.

Research aim and profile
According your characteristics, you have been confirmed or suspected as being diagnosed with an abdominal aortic aneurysm (AAA). AAA is a chronic progressive disease that occurs mostly among male above 65 years old. The incidences of AAA for male and female aged over 60 years were shown to 5% and 1%.
Invasive surgery or interventional therapy is not recommended to the "small" AAA (defined as the maximal aortic external diameter between 30 and 55 millimeters) without surgical indications for the benefit of surgery can't outweigh the rupture risk. Closely monitoring the growth rate of the AAA is recommended, surgical or interventional treatment is required as soon as possible if the diameter exceeds 55 mm, or the growth rate is too rapid.
A large number of evidences indicate that rivaroxaban could diminish high-sensitivity Creactive protein (hs-CRP) successfully to anti-inflammatory and prevent cardiovascular and cerebrovascular disease. So we invite you to participate in the BANBOO trial: A randomized, controlled study of rivaroxaban in patients with AAA and hs-CRP elevation. This is a clinical research study involving professional medical researchers. The study protocol has been approved by the Ethics Committee of General Hospital of Northern Theatre Command.
Before you decide whether to participate in the study, please read the following as carefully as possible. It can help you understand the study, why the study is being conducted, the process and duration of the study, the possible benefits and risks if you participate in the study. If you prefer, you can also discuss it with your relatives and friends, or ask your doctor for an explanation to help you make a decision. However, we cannot guarantee that rivaroxaban will work for you totally for 8 individual differences. If rivaroxaban does not work for your condition, you can ask your doctor about possible alternative treatments.

Protocols
This study was conducted in patients with AAA (aneurysm diameter of 30-50 mm) and hs-CRP elevation. The efficacy and safety of rivaroxaban in the treatment of AAA were investigated by the reduction degree of hs-CRP. Compared with aspirin group, the effect of rivaroxaban on preventing thrombosis and delaying disease evolution of AAA will be analyzed. This study was a prospective, single-center, open-label, randomized, controlled clinical trial.

4) Written Informed consent .
Unsuitable for participants in this study:

1) ACS (unstable angina and acute myocardial infarction);
2) Dual antiplatelet therapy for stable CHD less than 6 months after PCI or for ACS less than 1 year after PCI; 3) Acute congestive heart failure or left ventricular ejection fraction≤40%; 4) Suffer from infectious diseases within 2 months before screening and infection has not been controlled more than 1 month; 5) Active hepatitis , the elevation of alanine aminotransferase (ALT) values>5×the upper limit

Therapy procedure
If you meet the randomization criteria, you will be randomly assigned to either intervention (rivaroxaban) or control (aspirin) group. And then, if you are assigned to the intervention group, you will be treated with rivaroxaban tablets (XARELTO®, Bayer, 15mg once daily, 10mg for patients over 75 years of age); If you are assigned to the control group, you will be treated with aspirin enteric-coated tablets (BAYASPIRIN®, Bayer, 100mg once daily); Regardless of which group was assigned, pitavastatin calcium tablets (LiQingZhi®, Kowa Company Ltd., 2mg once daily) are administered.
All enrolled patients could complete 3 visits: the doctor will learn about your medication status, adverse events and relevant laboratory test items (include liver function, kidney function, hs-CRP, interleukin-6, coagulation, etc.) at 1 month and 6 months, all laboratory tests were routine tests of AAA. Imaging examination (CTA) at 6 months will be added as final visit.

Study time and number of patients
A total of 60 would be enrolled in the study. The approximate time span is 18 months.

Limitations and responsibilities of subjects
2.4.1 Before you are enrolled in this study, your medical history will be asked and recorded, and CTA examination and relevant laboratory tests will be performed to confirm the diagnosis of AAA. If your doctor determines that you are suitable to participate in the study according to the inclusion and exclusion criteria, you can voluntarily decide to participate in and sign the informed consent or not. If you do not wish to participate in the study, your doctor will respect your choice and follow the local treatment guidelines of AAA.
2.4.2 During the follow-up period, the doctor will inform you of the time of face-to-face followup via phone/Wechat. Your follow-up is very important, because the doctor will judge the treatment effect and adverse events of drugs you have received. You should not use other antithrombotic drugs during the study period. If you need extra treatment, please contact your doctor in advance for more reasonable advices.

Side effects and risks
Participants in both rivaroxaban and aspirin groups were at risk for adverse events, but this risk was not significant in many of the preliminary clinical trials. Both treatments are prone to bleeding. The risk of bleeding was considered when you were enrolled in the study, and your risk of bleeding is very low. There may be a risk of gastrointestinal bleeding in the aspirin group. Based on current evidence and guidelines, this increased risk is uncertain and can be prevented and controlled with proton pump inhibitors. Doctors will adopt appropriate treatment to the significant bleeding once occur.

Discomfort
If you experience any discomfort during the study period, whether or not related to the study, you should immediately contact your doctor, who will judge and administer appropriate medical treatment.

Your potential benefits
If you participate in the study, the researchers can closely monitor your disease progression and clinical events during the trial for you. If you feel uncomfortable during the trial, you can communicate with the doctor in time. Doctors monitor the dynamics of the condition at any time, master the best treatment strategy which is beneficial to you, so that you can get longterm benefits.

Compensation
The drugs used in this study are all conventional therapeutic drugs that have been on the market. All the examinations and laboratory tests involved are routine examinations and tests, you should bear your own expenses. Doctors will prevent possible adverse reactions, and if an adverse event occurs in a clinical trial, a committee of medical experts will determine whether it is related to rivaroxaban/aspirin. You will still bear the costs of treatment and examinations for other diseases that you have concomitant with.

Withdrawal
Participation in the study is entirely up to you. You may refuse to participate in the study or withdraw from the study at any time during the study, this will not affect your relationship with your doctor, and will not affect your treatment or other benefits.
The investigators may terminate your participated trial at any time during the study in your best interest. You may also be advised to have laboratory tests or a physical examination if your doctor deems it necessary.

Privacy
Your medical records (case reports, laboratory tests, etc.) will be kept completely in the General Hospital of Northern Theatre Command. Your doctor will record the results of laboratory and other tests on your medical record. Researchers, ethics committees, monitor and drug regulators will be allowed access to your medical record. Your personal identity will not be disclosed in any public report on the result of this study. We will do everything within the law to protect the privacy of your personal medical information. In accordance with the requirements of medical research ethics, except for personal privacy information, the trial data will be available for public inquiry and sharing, which will be limited to web-based electronic databases to ensure that no personal privacy information will be disclosed.

Answer questions about the study
You may ask any questions about this study at any working time and receive answers accordingly. If it is necessary to modify the content of the informed consent with unexpected clinical effects, you or your legal representative should sign again for confirmation. If there is 12 any significant new information during the study that may affect your willingness to continue to participate, your doctor will inform you promptly. Your doctor will be available to contact you in the event of an emergency.
It is up to you (and your family) to decide whether to participate in the study. Before you decide to join the study, ask your doctor as many questions as possible. Thank you for reading the above material and co-operation.
Please keep this document.
The present study has been approved on paper by Ethics Committee of General Hospital of Northern Theatre Command. If you have any questions about you rights in the study, please contact: Ethics Committee of General Hospital of Northern Theatre Command, No.83 Wenhua Road, Shenyang, Liaoning Province, 110016, Tel:+86-24-28856577